At the molecular level biological systems are highly asymmetric; enzymes, proteins, polysaccharides, nucleic acids, and many other fundamental components of life are present in optically active form. The implications of this are profound; as a general proposition the interaction of a chiral molecule with an optically active site is a diastereomeric interaction, and the two enantiomers properly should be viewed as distinct compounds capable of acting in different ways. (R)-Asparagine has a bitter taste, whereas the (S)-isomer is sweet. It has been known for some time that for medicinals having at least one chiral center the pharmacological effectiveness of the enantiomers of the racemic mixture may differ substantially, and in some cases the pharmacological action itself may differ. An extreme example is provided by propranolol, where the major pharmacological effect of the (R)-isomer is as a contraceptive, whereas the major pharmacological effect of the (S)-isomer is as a beta-blocker.
Although the recognition of the desirability of using the pharmacologically and pharmaceutically more acceptable enantiomer is old, nonetheless the use of optically pure medicinals generally is relatively new, simply because of the difficulty and cost of resolution of the racemic mixture and/or the difficulty and cost of asymmetric synthesis of the desired enantiomer. The importance of stereochemical purity may be exemplified by (S)-propranolol, which is known to be 100 times more potent as a beta-blocker than its (R)-enantiomer. Furthermore, optical purity is important since certain isomers actually may be deleterious rather than simply inert. For example, the R-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy. However, S-thalidomide was discovered to be a potent teratogen leaving in its wake a multitude of infants deformed at birth.
With recent chemical advances, especially in asymmetric synthesis, has come both an increase in the feasibility of selectively preparing the desired enantiomer of a given chiral medicinal, as well as increasing pressure on the pharmaceutical industry to make available only that enantiomer. Instructive examples, pertinent to the subject matter of this invention, are the antidepressant cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, (hereinafter, xe2x80x9csertraline, or where racemic, xe2x80x9cracemic sertralinexe2x80x9d), which has Formula I, and the class of compounds (hereinafter, xe2x80x9csertraline analogsxe2x80x9d or where racemic, xe2x80x9cracemic sertraline analogsxe2x80x9d) having Formula II. 
Thus, there is described in U.S. Pat. Nos. 4,536,518, and 4,556,676 to W. M. Welch, Jr., as well as in the paper of W. M Welch, Jr. et. al., Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508, (1984) a multi-step method for synthesizing pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine. An important synthetic step involves reduction of a precursor immine to the corresponding amine, which reduction results in a mixture of the cis and trans isomers in the form of a racemate. This isomeric mixture is then separated by chromatography on silica gel or by fractional crystallization of the hydrochloride salts. The cis racemate amine free base is then classically resolved with an optically-selective precipitant acid, as is known in the art, to yield sertraline.
The foregoing are examples of conventional synthesis and separation, as are known in the art, relevant to sertraline in which isomer separation of a sertraline precursor is performed by chromatography or by crystallization, and enantiomer separation leading to the final target medicinal sertraline is performed by optically-selective precipitation. Another approach of resolving a precursor is exemplified by the work of Schneider and Goergens, Tetrahedron: Asymmetry, No. 4, 525, 1992. These authors effected enzymatic resolution of 3-chloro-1-phenyl-1-propanol (CPP) via enzymatic hydrolysis of the racemic acetate in the presence of a lipase from Pseudomonas fluorescens under close pH control with a phosphate buffer. The hydrolysis was halted after about 50% conversion to afford the R-alcohol while leaving unchanged the S-acetate, which subsequently could be hydrolyzed with base to the S-alcohol. From the enantiomerically pure alcohols the enantiomerically pure serotonin-uptake inhibitors fluoxetine (whose racemate is available as Prozac(trademark)), tomoxetine, and nisoxetine could be prepared.
The Schneider and Goergens approach highlights a characteristic of methods based on resolution of a racemate, whether the racemate is that of a precursor or of a final medicinal compound, which requires our attention. The authors used both the R- and S-CPP to prepare both R- and S-fluoxetine in high optical purity, although one enantiomer is substantially more desirable than the other (see U.S. Pat. No. 5,104,899, supra). Consequently, in practice only, the more desirable enantiomer will be utilized, either in subsequent synthesis or as the final chiral medicinal. There then results the economic burden of discarding the less desirable (or even undesirable) enantiomer, whether of a precursor or of a final medicinal. Thus, it is imperative to somehow utilize the undesired enantiomer which results from resolution. Stated concisely, incident to a method of preparing medicinals of high optical purity based on resolution of a racemate of a raw material, intermediate or of a final medicinal, is the requirement of utilizing the unwanted enantiomer produced as a byproduct of the resolution stage. For a final medicinal compound, perhaps the most desirable utilization of the unwanted enantiomer would be to racemize it and recycle the racemate back to the separation stage; this application is directed precisely to such a process.
The purpose of the present invention is to present a process for the preparation of sertraline and for preparation of the more desirable enantiomers of sertraline analogs. One embodiment comprises separation of isomeric racemic sertraline or isomeric racemic sertraline analogs by simulated moving bed chromatography using a chiral or non-chiral adsorbent to afford at least one substantially pure racemic sertraline isomer or racemic sertraline analog isomer, resolution of a sertraline isomer racemate or sertraline analog isomer racemate by simulated moving bed chromatography using a chiral adsorbent to afford at least one substantially pure sertraline enantiomer pair or sertraline analog enantiomer pair, resolution of a sertraline enantiomer pair or sertraline analog enantiomer pair by simulated moving bed chromatography using a chiral adsorbent to afford substantially pure sertraline or at least one substantially pure sertraline analog, and conversion of less desirable isomers and/or enantiomers to a mixture of isomeric racemic sertraline or sertraline analogs, with recycle to the an appropriate resolution stage. In a specific embodiment cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine is utilized as the substantially pure sertraline enantiomer.